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256 10 The Use of SMB for the Manufacture of Enantiopure Drug Substances: From …

10.2 Chromatographic processes

10.2.1 SMB: Comparisons to Batch Chromatography

The purification of “value-added” pharmaceuticals in the past required multiple
chromatographic steps for batch purification processes. The design and optimization
of these processes were often cumbersome and the operations were fundamentally
complex. Individual batch processes requires optimization between chromato-
graphic efficiency and enantioselectivity, which results in major economic ramifica-
tions. An additional problem was the extremely short time for development of the
purification process. Commercial constraints demand that the time interval between
non-optimized laboratory bench purification and the first process-scale production
for clinical trials are kept to a minimum. Therefore, rapid process design and opti-
mization methods based on computer aided simulation of an SMB process will assist
at this stage.
Chromatography is a separation technique widely adopted not only at the analyt-
ical scale, but also at the preparative and large industrial scale. In this framework,
SMB technology is an established technique for continuous chromatographic manu-
facture of enantiopure drugs and other pharmaceuticals. Although SMB units are rel-
atively complicated, engineering issues at the scale of pharmaceutical production of
enantiopure drugs are well understood.
There are many advantages of the SMB technology compared to batch prepara-
tive chromatography. The process is continuous and the solvent requirement is min-
imal compared to batch. In SMB, the whole stationary phase is used for the separa-
tion while in batch chromatography only a small part of the column is involved in
the separation. This allows optimization of productivity with respect to the station-
ary phase.
At the current time, there is considerable interest in the preparative applications
of liquid chromatography. In order to enhance the chromatographic process, atten-
tion is now focused on the choice of the operating mode [22]. SMB offers an alter-
native to classical processes (batch elution chromatography) in order to minimize
solvent consumption and to maximize productivity where expensive stationary
phases are used.
SMB technology was introduced in the late 1950s [23] and has mainly been
applied to large-scale productions in the petrochemical and sugar industries [24].
SMB is recognized as a very efficient technology, but was ignored by the pharma-
ceutical and fine chemical industries mainly for patent reasons and complexity of
concept.
In 1993, shortly after the FDA announced their first policy statement on enan-
tiopure drugs, separations of pharmaceutical compounds were performed using
SMB technology [25, 26]. Other applications now include fine chemistry, cosmetics,
and perfume industry [27].